Sex Differences in the Excess Risk of Cardiovascular Diseases

Published online: 26 May 2015

# The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract Strong evidence suggests that type 2 diabetes confers a stronger excess risk of cardiovascular diseases in women than in men; with women having a 27 % higher relative riskof stroke and a 44 % higher relative risk of coronary heartdisease compared with men. The mechanisms that underpinthese sex differences in the associations between diabetes andcardiovascular disease risk are not fully understood. Some ofthe excess risk may be the result of a sex disparity in themanagement and treatment of diabetes, to the detriment ofwomen. However, accruing evidence suggests that real biological differences between men and women underpin theexcess risk of diabetes-related cardiovascular risk in womensuch that there is a greater decline in risk factor status inwomen than in men in the transition from normoglycemia toovert diabetes. This greater risk factor decline appears tobe associated with women having to put on more weight thanmen, and thus attain a higher body mass index, to developThis article is part of the Topical Collection on Diabetes+InsulinResistance* Sanne A. E. Peterspeters@georgeinstitute.ox.ac.uk1

IntroductionDiabetes mellitus is a major health concern; 382 million individuals or 8.3 % of the adult population worldwide have diabetes, and an additional 175 million people are unaware thatthey may have diabetes. Most people with diabetes live inlow- and middle-income countries; countries in Oceania,North Africa and the Middle East have the highest prevalenceof diabetes, with rates in these countries ranging from 2125 % in men and 2132 % in women (Fig. 1) [1, 2]. Theprevalence of diabetes is expected to rise by 55 % to 592million individuals by 2035 [1]; whilst much of this increaseis driven by population growth and ageing, other key contributors are the rapid growth in the prevalence of overweight andobesity and the increasing lack of physical activity. Trends inthe prevalence of diabetes vary substantially between regionsand sexes, which is inherent to substantial biological, socioeconomic and societal differences (Fig. 2) [2, 3]. Type 2 diabetes is the most common type of diabetes and accounts for 85to 95 % of all diabetes, with the remainder comprising mainlyof type 1 diabetesone of the most common autoimmunediseases.Diabetes and its complications are major causes of earlydeath in most countries. Approximately 5.1 million individuals died from diabetes in 2013, accounting for 8.4 % ofglobal all-cause mortality amongst adults [1]. Although the

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global number of deaths due to diabetes is similar between

men and women, there are important differences in the globaldistribution of these deaths [1]. About 25 % more men than

Fig. 2 Percentage growth in agestandardised diabetes prevalence,

19802008, by region.Reproduced, with the permissionof the publisher, from reference [3]

women die of diabetes in the Western Pacific region, whereas

diabetes accounts for 30 % more deaths in women than in menin Southeast Asia, and for over 50 % more deaths in women in

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Africa. This disparity may in part be due to higher rates of

mortality from other causes, biological factors, or because ofpoorer access to healthcare amongst women in some regions.Diabetes also poses a large economic and social burden onindividuals and families, national health systems and countries. Health spending on diabetes accounted for 11 % of totalhealth expenditure worldwide in 2013, equating to 548 billionUSD and, unsurprisingly, only 20 % of this global healthexpenditure occurred in low- and middle-income countries,where about 80 % of all individuals with diabetes live [1].Hence, whilst the impact of the diabetes epidemic is global,it disproportionally affects those living in socially and economically disadvantaged conditions.Sex Differences in the Excess Risk of CardiovascularDiseases Associated with Type 2 DiabetesConsiderable sex differences exist in the occurrence of thevarious manifestations of cardiovascular disease (CVD).Men have a higher risk of coronary heart disease (CHD),whereas women, who tend to have a longer life expectancy,have a similar or greater propensity of developing stroke [4,5]. Cardiovascular disease is the most common underlyingcause of death, accounting for 52 % of deaths in type 2 diabetes [6]. This estimate, however, is based on the assumptionthat the associations between diabetes and CVD outcomes areequivalent between women and men. An accruing body ofliterature shows that there are appreciable and clinically relevant differences in how diabetes affects the risk of CVD inmen and women (Fig. 3). A recent pooled analysissummarising data from 64 cohorts, including nearly 900,000individuals and over 28,000 incident CHD events, showedthat the presence of diabetes nearly tripled the risk of incidentCHD in women (RR 2.82 [95 % CI 2.35; 3.38]), whereas itlittle more than doubled the risk in men (RR 2.16 [95 % CIFig. 3 Relative risk (RR) andwomen:men ratio of relative risks(RRR) for coronary heart disease(CHD) and stroke in women andmen with diabetes versus withoutdiabetes. Vertical bars represent95 % confidence intervals. Datawere obtained from references[7, 9]

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1.82; 2.56]) [7]. Therefore, diabetes conferred a 44 % (95 %

CI 2763 %) greater excess risk for incident CHD in womencompared with men. This estimate is comparable to the 46 %excess risk for fatal CHD in women with diabetes found in aprevious analysis [8]. In addition, a pooled analysis on datafrom 750,000 individuals and more than 12,000 incidentstroke events provided strong evidence that women with diabetes mellitus have a 27 % (95 % CI 10, 46 %) greater increased risk of stroke compared with their male counterparts;the pooled relative risk of stroke associated with diabetes was2.28 (95 % CI 1.93, 2.69) in women and 1.83 (95 % CI 1.60,2.08) in men, independent of sex differences in other majorcardiovascular risk factors [9]. This sex differential was seenconsistently across major predefined stroke, study and participant subtypes, which included a comparison of individualsfrom Asian and non-Asian populations. Furthermore, recentanalyses of routinely collected health care data from the UKsuggests that diabetes has a stronger association with the riskof CVD in women than in men; however, only amongst youngpeople [10]. This may be explained by findings from previouslarge-scale studies that show that the effects of diabetes on therisk of CVD generally attenuate with age. Sex differences maycontinue to exist after the diagnosis of diabetes; a recent studysuggested that the risk of stroke associated with higher HbA1cwas greater in women than in men with type 2 diabetes; each1 % increase in baseline HbA1c was associated with a 5 %(95 % CI 1.02, 1.07) higher relative risk of stroke in womenand a 1 % (95 % CI 0.99, 1.04) higher relative risk of stroke inmen [11].Sex Differences in the Management of DiabetesA sex disparity in the management and treatment of cardiovascular risk factors in individuals with diabetes, to the detriment of women, possibly explains the excess risk of CVD in

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women with diabetes compared to men. Historically, women

with diabetes were more likely to have a more adverse cardiovascular risk profile, were treated less aggressively and wereless likely to achieve recommended levels of risk factors compared to male counterparts [1216]. Whilst access to treatmenthas become more equitable between the sexes over the pastdecade, especially in high income countries, sex differences inmedication use and risk factor control continue to exist [17,18]. For example, the 20122013 report of the National Diabetes Audit on nearly 2 million individuals with diabetes inthe UK showed that 58 % of women and 62 % of men withdiabetes received recommended care processes, and that 34 %of women and 37 % of men achieved treatment targets forHbA1c, blood pressure and cholesterol [17]. After controllingfor key confounding factors, such as age, ethnicity, deprivation group, body mass index (BMI) and duration of diabetes,women were 15 % less likely than men to meet all recommended care processes. Furthermore, other recent studieshave shown that, even when treated similarly, women withdiabetes are less likely than men to achieve target values forcardiovascular risk factors [19, 20]. We therefore hypothesisethat sex differences in the management of diabetes alone areunlikely to explain all of the excess relative risk of CHD andstroke in women with diabetes. This is also supported by theresults from the meta-analyses [7, 8, 9], which showed thatthe impact of accounting for levels of cardiovascular risk factors on the estimated excess risk of CHD and stroke associatedwith diabetes was similar in men and women.

risk factor levels between individuals with and without type

2 diabetes is greater in women than in men (Table 1) [2126].The British Regional Heart Study and British Womens Healthand Heart Study found that women with diabetes had greaterrelative differences in many established and novel cardiovascular risk factors than men with diabetes including markers ofcoagulation, fibrinolysis, lipids and blood pressure, whichwere potentially mediated by greater differences in centraladiposity and insulin resistance in women [23]. Hence, sincemany cardiovascular risk factors change to a greater extent inwomen than in men, women may have more cardiometabolicreserves and have to undergo greater metabolic deteriorationto develop diabetes than do men. This hypothesis is supportedby studies that found that levels of cardiovascular risk factorsare already different between men and women before the conversion to a state of impaired glucose tolerance [27, 28].Women, but not men, who progress from normoglycemia topre-diabetes have higher levels of endothelial dysfunction,higher blood pressure and more abnormalities in their fibrinolysis and thrombosis pathways, compared to those who do not[28]. Therefore, the diabetes-related excess risk of CVD inwomen may not necessarily be due to any significant sexdifference in the effects and complications of diabetes itself,but rather the result of a greater deterioration in cardiovascularrisk factor levels in women compared to men in the transitionto diabetes. Consequently, women diagnosed with diabetesmay already be at a worse starting point than comparablemen before treatment begins.

Sex Differences in Cardiovascular Risk Factors

in the Development of Diabetes

Sex Differences in Body Mass Index at the Time

of Diagnosis

Women without diabetes generally have more favourable

levels of cardiovascular risk factors than men, but this patternmay reverse with a decline in glucose tolerance [8, 9]. Severalstudies have shown that the deterioration in cardiovascular

Overweight and obesity is the key risk factor for the development of diabetes. Even though the magnitude of the association between BMI and diabetes is similar in men and women,studies have demonstrated that men need to attain a lower

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average BMI to be diagnosed with diabetes compared to

women [29, 30]. For example, in a population-based diabetesregister in Scotland, mean BMI closest to date of diagnosis oftype 2 diabetes mellitus was 31.8 kg/m2 in men and 33.7 kg/m2 in women (Fig. 4) [30]. Results from the UK GeneralPractice Research Database were almost identical to theseScottish findings; the age-adjusted average BMI at diagnosisof diabetes was nearly 2 kg/m2 higher in women than in men[29]. Both studies demonstrated that the difference in BMI atthe time of diagnosis of diabetes was most marked at youngerages and narrowed with advancing age. Moreover, the Scottish data showed that HbA1c levels within 1 year of diagnoseswere broadly similar in men and women, indicating that theywere diagnosed at a similar stage of disease [30]. This impliesthat, at the same level of BMI, adult men without diabetes aremore resistant to insulin than women or, similarly, that adultwomen are at lower risk of diabetes at an equivalent BMI.The sex disparity in BMI at the time of diagnosis of diabetes can be linked to differential patterns of adiposity storage inmen and women, and also to a healthier CVD risk profile inwomen without diabetes versus their male counterparts, asdiscussed above [31, 32, 33]. Women, in general, have greater subcutaneous fat storage capacities and, linked to this, carryless visceral (i.e. more hazardous) fat than men. Since subcutaneous storage capacity is lower in men, excess adipose tissueis placed more rapidly into visceral and ectopic tissues, suchas the liver and the skeletal muscle, which in turns leads toFig. 4 Mean body mass index byage at diagnosis of type 2 diabetesfor men (black) and women(white) aged between 30 and90 years at diagnosis and withBMI >25 kg/m2 from the ScottishCare Information DiabetesCollaboration (SCI-DC) dataset.Patients who died within 2 yearsof BMI determination wereexcluded. Vertical bars represent95 % CIs around the mean.Reproduced, with the permissionof the publisher, from reference[30]

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insulin resistance and interferes with insulin signalling pathways [34]. Women need to accumulate a greater amount oftotal adiposity, i.e. require attaining a higher level of BMI,than men for their subcutaneous storage to become exhausted,and to reach the same harmful visceral and ectopic fat deposition required to become insulin resistant and to develop diabetes [32, 34]. Moreover, women, on average, tend to have agreater deterioration in metabolic risk factors including levelsof blood pressure, lipids and inflammatory markers, and arelikely to have accumulated more time living in a hazardousmetabolic environment exacerbated by being in a pre-diabeticstate compared with men in whom the deterioration in metabolic indices is less marked. This sex difference in the preferential location of fat storage (subcutaneous in women versusvisceral/ectopic in men) and its associated metabolic changesmay be crucial to the differential rates of development of diabetes (lower diabetes incidence in adult women) and, oncediabetes ensues, to differential complication rates as discussedherein.Clinical ImplicationsDiabetes develops over decades; a recent study demonstratedthat men, on average, have pre-diabetes for 8 years, and women for 10 years before they progress to overt diabetes [35].This window presents an opportunity for identifying individuals at high risk for diabetes, and subsequently, for timely

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intervention to prevent or delay the onset of diabetes. The

widening acceptance of diabetes diagnosis and its high riskstates, via either fasting glucose (5.5 to 6.9 mmol/L as highrisk) or HbA1c (6.0 to 6.4 % as high risk), has facilitatedscreening for, and diagnosis of, diabetes in clinical practise[36, 37]. HbA1c has the advantage of not requiring individuals to fast, enabling diagnosis to be done at any time and inany clinical situation, thus improving early detection of highrisk for, or existing, diabetes. What is needed now is betterfacilitation of lifestyle changes to help men and women at riskto favourably change their weight, or weight trajectory, todelay or prevent the onset of diabetes. There is evidence thatcommercial weight loss companies do better than routine clinical services in helping people to lose weight and that women,in particular, are more comfortable with such services [38].Similarly, increased awareness of the magnitude and timing ofthe risk of diabetes after gestational diabetes could provide anopportunity to facilitate lifestyle interventions that might prevent or delay the onset of type 2 diabetes in affected women[39, 40]. Regular monitoring of HbA1c in women with gestational diabetes will help facilitate risk screening. As cardiovascular risk factors escalate more in women as they transitionto diabetes, physicians should take particular care to conduct acomprehensive cardiovascular risk assessment in women(whilst not neglecting men) noted to be at elevated risk ofdiabetes. These ideas fit with the need, wherever possible, tocombine risk assessments for CVD and diabetes in primarycare, in simple and pragmatic ways, as recently argued [41].Finally, all physicians should be made aware that developmentof diabetes is associated with a greater increase in cardiovascular risk in women than in men so that they should, at thevery least, treat women with diabetes as aggressively as theydo with their male counterparts.

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needed to improve the prevention and management of diabetes in clinical practise.

Compliance with Ethics GuidelinesConflict of Interest Mark Woodward reports personal fees fromNovartis, personal fees from Amgen, from Sanofi, outside the submittedwork. Naveed Sattar, Sanne Peters and Rachel Huxley have no competinginterest to report.Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by theauthors.Open Access This article is distributed under the terms of theCreative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricteduse, distribution, and reproduction in any medium, provided you giveappropriate credit to the original author(s) and the source, provide a linkto the Creative Commons license, and indicate if changes were made.

ReferencesPapers of particular interest, published recently, have beenhighlighted as: Of importance

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Conclusion5.

There is accumulating evidence that the impact of type 2 diabetes on cardiovascular risk differs profoundly between thesexes and is more hazardous for women than for men. Although this may in part reflect a treatment disparity betweenwomen and men with diabetes, there are several lines of evidence to suggest that real behavioural and biological sex differences exist which may underpin the excess risk of diabetesrelated cardiovascular risk in women. A greater deteriorationin risk factor status in women than in men as they transitionto diabetes, before the development of overt diabetes,appears to play a crucial role. This greater risk factor declinemay in turn be related to women having to put on more weightthan men (and thus attain a higher BMI) to develop diabetes.Future work aimed further clarification and understanding ofthe mechanisms responsible for sex differences in the excessrisk of cardiovascular diseases associated with diabetes will be